Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic adjuvant therapy is recommended immediately following surgical removal of the primary tumour in the majority of patients with early breast cancer, to prevent the recurrence of distant metastases. Significant progress has been made in the development and evaluation of endocrine therapies for systemic adjuvant therapy. In pre- and perimenopausal women, ovarian ablation has proven to be a valuable treatment option, though not always desirable for young patients. Thus, reversible medical ovarian suppression with a luteinizing hormone releasing hormone agonist, such as goserelin (Zoladex), may provide an attractive alternative for such patients. International trials have indicated that goserelin provides an important addition to the choice of adjuvant therapies now available to pre- and perimenopausal patients. For postmenopausal patients, it is hoped that the ATAC (Arimidex, tamoxifen, alone or in combination) trial will reveal whether or not the benefits of anastrozole (Arimidex) observed in advanced disease, where it has proven to be well tolerated and at least as effective as tamoxifen in recent trials, will translate to the early setting to provide further management options for these patients. On the horizon is yet another exciting endocrine agent, ICI 182,780 (Fulvestrant), which has also been shown to be as effective as anastrozole in advanced disease. In terms of the future, these agents are likely to provide additional valuable treatment choices for early breast cancer across the patient spectrum.
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PMID:A vision for the future? 1190 Feb 11

Patients with hormone-sensitive breast cancer who have responded to tamoxifen may receive additional benefit from a second endocrine agent following progression or relapse after tamoxifen therapy. Fulvestrant (Faslodex((R)), ICI 182780, AstraZeneca Pharmaceuticals; Wilmington, Delaware) is a selective antagonist of estrogen designed to have no estrogenic effects. Lack of aqueous solubility led to the development of a parenteral formulation for monthly intramuscular administration. Fulvestrant has been shown to inhibit the proliferative effects of estrogen on sensitive tissues in vitro and in vivo, and is without apparent measurable estrogenic activity. The data upon which marketing approval for fulvestrant was based are summarized below. Eight hundred fifty-one postmenopausal women with advanced breast cancer were enrolled in two phase III studies, 400 in a North American double-blind study and 451 in a European open-label study, comparing the efficacy and safety of fulvestrant with anastrozole. Four hundred twenty-eight patients were randomized to receive fulvestrant 250 mg monthly by intramuscular injection and 423 patients were to receive anastrozole 1 mg daily. Patients were considered hormone sensitive either by receptor status or previous response to endocrine therapy. Over 96% of patients had previously received tamoxifen, either in the adjuvant setting or as treatment for metastatic disease. The primary study end points were response rate and time to progression. Response rates for patients treated with fulvestrant were 17% and 20% in the North American and European trials, respectively, compared with 17% and 15% in the anastrozole treatment arms. There were no statistically significant differences in response rates, time to progression, or survival between treatment arms in either study. The most common adverse events attributed to the treatment (>10%) were injection-site reactions and hot flashes. Common events (1%-10%) included asthenia, headache, and gastrointestinal disturbances (nausea, vomiting, and diarrhea), as well as rash and urinary tract infections. A small increase in joint disorders was reported in the anastrozole-treated patients. On April 25, 2002, fulvestrant 250 mg by monthly intramuscular injection was approved by the U.S. Food and Drug Administration for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Approval was based on similarity of response rates and time to progression between fulvestrant and anastrozole.
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PMID:FDA drug approval summaries: fulvestrant. 1249 Jul 35

Endocrine therapy remains an important approach to the treatment of metastatic breast cancer because of its effectiveness and excellent tolerability. In the last 10 years, a number of new endocrine therapies have been introduced. These include the luteinizing hormone-releasing hormone agonists, which produce menopausal changes in premenopausal women; the aromatase inhibitors, which prevent production of estrogen in postmenopausal women; and the estrogen receptor down-regulator fulvestrant (Faslodex), which is effective in postmenopausal women whose tumors have progressed following response to other selective estrogen receptor modulators. The endocrine cascade for the treatment of premenopausal women with metastatic disease now involves the concurrent or sequential combination of a luteinizing hormone-releasing hormone analogue and tamoxifen, whereas the cascade for the treatment of postmenopausal women can begin with tamoxifen followed by an aromatase inhibitor or with an aromatase inhibitor followed by tamoxifen. The optimal cascade following the use of an aromatase inhibitor and tamoxifen in postmenopausal women remains unclear, but fulvestrant and megestrol acetate or the use of an aromatase inactivator (exemestane) following an aromatase inhibitor are all available options with some activity. Over the next few years, clinical trials will clarify the optimal sequence of endocrine therapy for postmenopausal women. The use of estrogen and progesterone receptor status to select for endocrine therapy is undeniably crucial. HER2/neu overexpression may also predict response to endocrine therapy, but this remains controversial.
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PMID:Endocrine therapy of advanced disease: analysis and implications of the existing data. 1253 1

The efficacy of fulvestrant (Faslodex), a novel oestrogen receptor (ER) antagonist that downregulates the ER and has no known agonist effects, was compared with the aromatase inhibitor anastrozole (Arimidex) for the second-line treatment of advanced breast cancer in postmenopausal women with visceral and non-visceral metastases. Assessment was by means of a retrospective subgroup analysis of combined data from two randomised, phase III trials. Objective response (OR) rates were similar in patients treated with fulvestrant and anastrozole, respectively (21.9% versus 19.3%-patients with no visceral metastases; 15.7% versus 13.2%-all of the patients with visceral metastases; 18.8% versus 14.0%-patients with visceral metastases only). The proportion of patients with clinical benefit (CB) was also similar between treatments and between subgroups with and without visceral disease. Fulvestrant is at least as effective as anastrozole, providing a valuable treatment option for advanced breast cancer in postmenopausal women with visceral metastases who have failed on prior endocrine therapy.
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PMID:Fulvestrant (Faslodex) versus anastrozole for the second-line treatment of advanced breast cancer in subgroups of postmenopausal women with visceral and non-visceral metastases: combined results from two multicentre trials. 1276 10

The use of adjuvant endocrine therapy in the treatment of hormone receptor-positive, early breast cancer has become important in both pre- and postmenopausal women. Tamoxifen has been the principal adjuvant hormonal therapy in pre- and postmenopausal women with hormone receptor-positive breast cancer for nearly 20 years. Recent data in premenopausal women suggest benefit from ovarian ablation with or without tamoxifen. Early results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial have demonstrated that the third-generation, selective aromatase inhibitor (AI) anastrozole ('Arimidex') is a suitable alternative adjuvant therapy for postmenopausal women with hormone receptor-positive disease. After recurrence or relapse on adjuvant endocrine therapy, responses to the sequential use of additional endocrine agents are common. The increase in the number of options now available for adjuvant therapy will have important implications for the selection of the optimal sequence of endocrine agents in the treatment of recurrent breast cancer. Menopausal status is an important factor in determining the endocrine therapy that a patient receives. For premenopausal women, tamoxifen and/or a luteinizing hormone-releasing hormone agonist such as goserelin ('Zoladex') are both options for adjuvant endocrine treatment. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women who have undergone ovarian ablation, the use of third-line therapy with an AI becomes possible. For postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant anastrozole. In addition, data suggest that fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist that downregulates the ER protein and has no known agonist effects, is a promising therapeutic option that has shown efficacy in the treatment of postmenopausal women with advanced breast cancer. Other agents that may be used in the sequence include the steroidal AI exemestane and the progestin megestrol acetate. The widening range of adjuvant endocrine options therefore represents an opportunity to prolong patient benefits in the treatment of hormone receptor-positive breast cancer, and will require the further refinement of the optimal sequence of endocrine agents for the treatment of recurrent breast cancer.
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PMID:Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole. 1453 31

Fulvestrant, a novel antiestrogen classified as an estrogen receptor antagonist without known agonist effects, was recently approved in the United States for the treatment of postmenopausal, hormone receptor-positive women with progressive metastatic breast cancer after antiestrogen therapy. In a phase II trial, monthly administration of fulvestrant, 250 mg intramuscularly, conferred clinical benefit (partial response or stable disease for >or= 24 weeks) in 69% of patients with tamoxifen-resistant advanced breast cancer. Furthermore, the median duration of response and survival for this population (26 and 54 months, respectively) was twice as high as those documented for a megestrol acetate-treated historical cohort (14 months and 30 months, respectively). Comparative phase III trials conducted in North America and internationally, which used time to progression as the primary endpoint, demonstrated fulvestrant's tolerability and equivalence to anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer, which led to its approval in this setting. Vasodilation and nausea were the principal treatment-related adverse events in the fulvestrant arms, and mild injection-site reactions occurred in 4.6% and 1.1% of monthly fulvestrant courses given in the North American and international trials, respectively. Recent subanalyses of the pivotal phase III data have found that fulvestrant produces a 30% longer mean duration of response compared with anastrozole and that fulvestrant-induced estrogen receptor downregulation does not preclude response to subsequent hormonal therapy. Ongoing trials in patients with advanced breast cancer will provide further insight into the relative merits of fulvestrant versus tamoxifen as first-line therapy for metastatic disease, the use of fulvestrant within combination and sequential regimens, and the efficacy of fulvestrant specifically in premenopausal women. Research efforts focusing on alternate administration schedules for fulvestrant and its potential as an adjuvant hormonal therapy are also anticipated.
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PMID:Fulvestrant: an estrogen receptor antagonist that downregulates the estrogen receptor. 1461 22

Fulvestrant (Faslodex) is a novel estrogen receptor (ER) antagonist that competitively binds to the ER with a much greater affinity than that of tamoxifen. The downregulation of cellular levels of the ER protein results in complete abrogation of estrogen-sensitive gene transcription. This distinct mechanism of action ensures a lack of cross resistance with other hormonal agents and, in contrast to tamoxifen, fulvestrant has no known estrogen-agonist effects. Fulvestrant is administered via monthly intramuscular injections (250mg) and is recommended for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. The efficacy of fulvestrant was similar to that of the aromatase inhibitor anastrozole (1 mg/day) in two, well designed studies in postmenopausal women with locally advanced or metastatic breast cancer that had progressed during prior antiestrogen therapy. Time to disease progression (primary endpoint) and treatment failure, rates of objective response and clinical benefit, overall survival and quality of life were similar in patients treated with fulvestrant or anastrozole. In retrospective noninferiority analyses, fulvestrant was at least as effective as anastrozole in all randomised patients, and in those with or without visceral metastases. Fulvestrant is generally well tolerated and was tolerated as well as anastrozole in clinical trials. Treatment-related adverse events were mostly mild to moderate and led to treatment withdrawal in about 1% of patients who received fulvestrant or anastrozole. The main adverse effects associated with therapy are nausea, asthenia, pain, vasodilation and headache.In conclusion, monthly intramuscular injections of fulvestrant are at least as effective and as well tolerated as oral anastrozole once daily in the treatment of postmenopausal women with advanced breast cancer that has progressed on prior antiestrogen therapy. Because of a different mode of action to that of other hormonal agents, fulvestrant is effective in the treatment of tamoxifen-resistant disease and, unlike tamoxifen, has no known estrogen agonist effects. Thus, fulvestrant provides an effective and well tolerated option for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
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PMID:Fulvestrant: a review of its use in hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. 1501 96

Fulvestrant ('Faslodex') is a new estrogen receptor (ER) antagonist that has no agonist effects. It binds, blocks and accelerates degradation of the ER, leading to a complete abrogation of estrogen-sensitive gene transcription. In postmenopausal women with advanced breast cancer progressing on prior endocrine therapy, fulvestrant is at least as effective as the third-generation aromatase inhibitor (AI) anastrozole. In this single-center experience, 42 postmenopausal patients with metastatic breast cancer who had been heavily pretreated with prior endocrine therapy and chemotherapy were treated with fulvestrant. Prior endocrine therapies included selective ER modulators (including tamoxifen and toremifene), AIs, megestrol acetate, and high-dose estrogens. In total, eight patients (19%) achieved stable disease (SD) for > or =24 weeks, including two patients with SD for 2 years and one with SD for 14 months. Fulvestrant was well tolerated with the majority of adverse events related to the site of metastatic disease. These data demonstrate that fulvestrant is a well tolerated and effective endocrine therapy for postmenopausal women with metastatic breast cancer who have been heavily pretreated with prior therapies. The novel mechanism of action of fulvestrant reduces the likelihood of cross-resistance with other endocrine therapies and therefore this agent may be active in patients who have proved to be resistant to treatments such as tamoxifen or AIs. The use of fulvestrant earlier in the sequence of endocrine treatments may achieve better responses than observed in this heavily pretreated patient population.
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PMID:Response to fulvestrant in heavily pretreated postmenopausal women: a single-center experience. 1556 93

Tamoxifen is the most widely prescribed anti-neoplastic drug for the treatment of both localized and metastatic breast cancer. It is also the prototype for a class of drugs that are referred to as selective estrogen receptor modifiers (SERMs), most of which have both estrogenic and anti-estrogenic activity in estrogen target tissues including the breast and endometrium. The underlying mechanisms of action of SERMs in the breast and endometrium that lead to profound differences in the tissue-specific effects of tamoxifen have not yet been elucidated. We have compared the effects of tamoxifen and the pure anti-estrogen ICI 182,780 (Faslodex) in the RUCA-I hormone-responsive rat endometrial cell line in vitro and in vivo. In cell culture, RUCA-I cells responded to both estrogens and anti-estrogens, and the expression of clusterin and complement C3 mRNAs required the presence of estradiol and was repressed in the absence of estradiol or in the presence of the pure anti-estrogen ICI 182,780. Tamoxifen, on the other hand, induced both complement C3 and clusterin mRNA in the absence of estradiol and failed to repress their expression in the presence of estradiol. When grown as subcutaneous xenografts in syngeneic Da/Han rats for 5 weeks, the RUCA-I cells retained their sensitivity to estradiol, as demonstrated by significantly enhanced tumor growth in intact female rats compared with the growth in ovariectomized rats. But neither ICI 182,780 nor tamoxifen had a significant impact on tumor growth in cycling or ovariectomized animals. On the other hand, tamoxifen was potently estrogenic in metastatic lymph nodes, increasing the size of the lymph node tumors almost 6-fold over that seen in the intact cycling animals. In primary tumors, the expression of complement C3 mirrored that seen in vitro, although tamoxifen showed some agonist activity in ovariectomized animals. Tamoxifen also displayed marked agonist activity with respect to clusterin expression and enhanced clusterin mRNA levels and protein in both the primary tumors and lymph metastases in intact and ovariectomized animals. Given the recent demonstration that over-expression of clusterin increases the metastatic potential of breast cancer cells, these data may provide a mechanistic explanation for the increased incidence of endometrial cancer in postmenopausal patients treated with tamoxifen.
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PMID:Tamoxifen exerts agonistic effects on clusterin and complement C3 gene expression in RUCA-I primary xenografts and metastases but not normal uterus. 1561 55

Fulvestrant, an estrogen receptor antagonist with no known agonist effects, is effective and well tolerated in the treatment of hormone-sensitive breast cancer after antiestrogen failure in postmenopausal women. Numerous phase II and III clinical trials of fulvestrant that are designed to build on its efficacy in breast cancer and explore its value in other tumors are ongoing or in the final planning stage. Favorable safety, dose-response, and pharmacokinetic data led to the initiation of clinical trials to evaluate loading and higher doses with the aim of building on the well-defined efficacy of fulvestrant. Recently reported results of phase II trials by the North Central Cancer Treatment Group and the Swiss Group for Clinical Cancer Research support the clinical activity of fulvestrant after recurrence or progression on a nonsteroidal aromatase inhibitor, and 2 international phase III trials are ongoing in this setting. As a first-line treatment for metastatic disease, fulvestrant is currently being evaluated in combination with anastrozole versus anastrozole alone in 2 phase III trials, 1 by the Southwest Oncology Group and the other being conducted mainly in Scandinavia. Preclinical data have also led to randomized phase II trials of fulvestrant in combination with the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib, and the HER2/neu-targeted antibody trastuzumab. Additional phase II and III trials are currently evaluating fulvestrant plus tipifarnib, Theratope vaccine, or the dual kinase inhibitor, GW572016. Although fulvestrant is undergoing robust clinical development as a treatment for breast cancer, investigation of this agent in other types of solid tumors has only just begun.
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PMID:Current and future perspectives on fulvestrant. 1586 48


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